Egypt J Pediatr Allergy Immunol 2014; 12(1):3-12. Review article Leukotrienes and leukotriene modifiers in pediatric allergic diseases Dalia H. El-Ghoneimy, Zeinab A. El-Sayed Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Cairo, Egypt Abstract substrate.5 Arachidonic acid, which is esterified on Leukotrienes are potent pro-inflammatory lipid plasma membrane phospholipids, is cleaved by the mediators derived from arachidonic acid through action of different phopsholipase A2 enzymes, several enzymatic pathways. They have an essential released and metabolized into LTA4. 2 LTA4 is role in allergic inflammation, where they induce converted by LTA4 hydrolase to LTB4, or it can be bronchoconstriction, airway edema, and conjugated with reduced glutathione by LTC4 chemotaxis of the inflammatory cells in the airways, synthase to yield LTC4. LTB4 and LTC4 are nasal and conjunctival tissues. Leukotriene exported from the cell by specific transporter modifiers include leukotriene receptor antagonists proteins; the released LTC4 is converted to LTD4 (montelukast, zafirlukast and pranlukast) and which undergoes conversion to LTE4 by sequential leukotriene synthesis inhibitors (zileuton). These amino acid hydrolysis.3 LTA4 is highly reactive, medications have been extensively used in with an estimated half-life less than 3 seconds. childhood allergic diseases. This review will LTC4 and its metabolites, LTD4 and LTE4, are highlight the leukotriene pathway and its role in known as cysteinyl-LTs due to the common allergy as well as the effects of leukotriene cysteine in their side chains.6 modifiers in different allergic disorders. The enzyme 5-LO is mainly expressed in granulocytes, monocytes, macrophages, mast-cells Allergic inflammation is due to a complex interplay and B lymphocytes.7 Mast cells and eosinophils can between several inflammatory cells, including mast produce large amounts of LTC4 from an cells, basophils, lymphocytes, dendritic cells, endogenous pool of arachidonic acid. Human eosinophils, and sometimes neutrophils. These cells bronchial fibroblasts constitutively express 5-LO, produce multiple inflammatory mediators, FLAP, LTA4 hydrolase, and LTC4 synthase and including lipids, purines, cytokines, chemokines, produce cysteinyl-LTs and LTB4 spontaneously in and reactive oxygen species. Allergic inflammation vitro.8 affects target cells, such as epithelial cells, Although nonleukocyte cells generally do not fibroblasts, vascular cells, and airway smooth have sufficient 5-LO and FLAP to synthesize muscle cells, which become an important source of appreciable amounts of leukotrienes from inflammatory mediators.1 Leukotrienes are potent arachidonate, such cells expressing distal LTA4- newly formed lipid mediators that are derived from metabolizing enzymes can take up leukocyte- arachidonic acid upon cellular activation, including derived LTA4 and metabolize it into bioactive IgE receptor cross-binding on mast cell surface.2 leukotrienes, a process that is termed transcellular Leukotrienes (“leuko,” from white blood cells; biosynthesis.6 and “trienes,” three conjugated double bonds) Leukotrienes and cytokines can regulate each comprise a family of products of the 5-lipoxygenase other; interleukin-13, a product derived from type 2 (5 Lipo-pathway of arachidonic acid metabolism.3 helper T (Th2) lymphocytes that participates in the They are divided into two classes: the development of asthma, can up-regulate both the chemoattractant LTB4 and the spasmogenic leukocyte biosynthesis of LTD4 and the expression cysteinyl leukotrienes [CysLTs: LTC4, LTD4, and of cellular type 1 Cys LT receptors (CysLT1). LTE4] which have been termed previously as slow- Moreover, LTD4 can up-regulate production of reacting substance of anaphylaxis (SRS-A).4 interleukin-13, as well as the expression of its receptor. The result of this cross-talk is a self- Biosynthesis of leukotrienes (figure1) perpetuating circuit of inflammation and smooth- The synthesis of leukotrienes from arachidonic acid muscle contraction in which interleukin-13 and its is initiated by 5-lipoxygenase (5-LO) in concert receptor mediate some of the actions of LTD4, with 5-lipoxygenase–activating protein (FLAP). whereas LTD4–CysLT1 mediates some of the Although FLAP does not have enzymatic activity, it actions of interleukin-13.3 enhances the ability of 5-LO to interact with its 3 El-Ghoneimy and El-Sayed Figure 1. The main pathways to the formation of the leukotrienes and the sites of action of the current drug groups (in boxes) that can attenuate leukotriene responses (Quoted from O’Donnell SR. Leukotrienes: Biosynthesis and mechanisms of actions. Aust Prescr 1999; 22: 55-7. ) Receptors of leukotrienes (T and B lymphocytes) immune systems, implying Leukotrienes act by binding to specific heptahelical potentially cooperative functions in immunity and receptors of the rhodopsin class that are located on inflammation.9 the outer plasma membrane of structural and CysLT1 receptor binds LTD4 with high inflammatory cells.9 Once ligated by the affinity and LTC4 with lesser affinity, whereas leukotriene, these receptors interact with G proteins CysLT2 receptor binds both LTC4 and LTD4 with in the cytoplasm, thereby eliciting increases in equal affinities. Neither receptor exhibits intracellular calcium and reductions in intracellular substantial affinity for LTE4 in radioligand binding cyclic AMP. These proximal signals activate assays nor does LTE4 elicit strong signalling downstream kinase cascades in ways that alter responses in cells expressing CysLT1 or CysLT2 in various cellular activities, ranging from motility to isolation.11, 13 Increased vascular permeability transcriptional activation.3 induced by LTE4 in mice lacking CysLT1 and Two G-protein coupled receptor subtypes for CysLT2 receptors suggests the existence of a third CysLTs (CysLT1 and CysLT2), that have 38% CysLT receptor that responds preferentially to amino acid identity, have been identified. 10 The LTE4.14 Certain reported actions of CysLT are not CysLT1 and CysLT2 receptors are broadly readily explained by either CysLT1 or CysLT2, expressed by structural and hematopoietic cells. raising the possibility of the presence of CysLT1– Some cell types (vascular smooth muscle) express CysLT2 heterodimers or additional receptors.15 One mostly Cys-LT1 receptors11, whereas others candidate is G protein–coupled receptor 17 (endothelial cells) dominantly express CysLT2 (GPR17), a dual-uracil nucleotide–CysLT receptors.12 Both receptors are expressed by cells of receptor.16 the innate (macrophages, monocytes, eosinophils, Two LTB4 receptor subtypes (BLT1 and basophils, mast cells, dendritic cells) and adaptive BLT2), that are cell surface G protein-coupled 4 Leukotriene modifiers and allergy seven transmembrane domain receptors, have been (BLT1) on target cells.23 LTB4 can have a central identified. These receptors differ in their affinity role in the neutrophilic inflammation that and specificity for LTB4 and their expression characterises severe asthma and asthma pattern. BLT1, a specific high affinity receptor for exacerbations.24 LTB4, is expressed predominantly on leukocytes CysLT levels were found to be elevated in including granulocytes, monocytes, macrophages, bronchoalveolar lavage25 and induced sputum26 mast cells, dendritic cells, and effector T cells,17 from patients with asthma, when compared with whereas BLT2, a low affinity receptor which can levels in healthy volunteers at baseline and also bind to other eicosanoids, is expressed following exercise27 or allergen challenge.28 In ubiquitously and their biological role in humans is patients with allergic rhinitis, specific allergen unknown.18 challenge provoked significant increases in nasal airway resistance, numbers of neutrophils and Role of leukotrienes in allergic inflammation eosinophils, and levels of protein, histamine, LTB4, CysLT1 receptor mediates sustained broncho- and CysLTs in nasal lavage fluid.29 Also, LTB4 was constriction, mucus secretion, and edema in the found to cause eosinophil and neutrophil emigration airways (figure 2).19 CysLT inhalation in patients into conjunctival tissue. LTB4 and LTC4 levels with asthma increases the number of sputum were reported to be increased in the tears of patients eosinophils and causes recruitment of eosinophils with seasonal allergic conjunctivitis.30,31 into the airway mucosa. 20 CysLTs prime progenitor Several in vivo and in vitro studies suggest that cells to differentiate into mature blood cells, cause leukotrienes are involved in the inflammation of the chemotaxis of eosinophils increasing their cellular skin in atopic dermatitis, possibly by chemotaxis of adhesion and transendothelial migration across the inflammatory cells, vasodilatation and oedema, but vessel wall into the airways, increase eosinophil their role is controversial.32 The enzymatic activities survival in response to mast cell and lymphocyte of LTA4 hydrolase in peripheral blood leukocytes paracrine signals and activate eosinophils, mast were found to be associated with disease severity in cells, T-lymphocytes, monocytes and basophils. 21,22 patients with atopic dermatitis and were reduced LTB4 serves as a potent chemoattractant through after improvement of the disease.33 ligation of the high affinity LTB4 receptor-1 Figure 2. Leukotriene actions on airway structure. (Hay DW, Torphy TJ, Undem BJ. Cysteinyl leukotrienes in asthma: old mediators up to new tricks. Trends Pharmacol Sci. 1995,16:304-9). 5 El-Ghoneimy